25 February 2022

The protective armour of superbug C.difficile revealed

The spectacular structure of the protective armour of superbug C.difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like chain mail.

Artist illustration of the chain-mail like structure of the bacteria
Credit - Newcastle University/Dr. Lizah van der Aart
  • Scientists have uncovered the close-knit outer structure of the superbug C.difficile
  • The chain mail like structure protects the diarrhoea-causing superbug from our immune system and drugs which fight the bacteria 
  • This discovery could pave the way for developing new treatments that are able to break this structure and kill the cell

The spectacular structure of the protective armour of superbug C.difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like chain mail.

This assembly prevents molecules from getting in and attacking the superbug, but also provides a new target for future treatments, according to the scientists who have uncovered it.

Publishing in Nature Communications, the team of scientists from Sheffield, Newcastle and Glasgow Universities, together with colleagues from Imperial College and Diamond Light Source, outline the structure of the main protein, SlpA, that forms the links of the chain mail and how they are arranged to form a pattern and create this flexible armour. 

This opens the possibility of designing C. diff specific drugs to break the protective layer and create holes to allow molecules to enter and kill the cell. 

Protective armour is one of the many ways that diarrhoea-causing superbug Clostridioides difficile has to protect itself from antibiotics. The S-layer is a special layer that covers the cell of the whole bacteria. This flexible armour protects against the entry of drugs or molecules released by our immune system to fight bacteria.

The team identified the structure of the proteins and how they are arranged using a combination of X-ray and electron crystallography.

Dr Rob Fagan, Professor Per Bullough, Dr Oishik Banerji and Dr Jason Wilson from the University of Sheffield's School of Biosciences, carried out the electron crystallography work.

Dr Fagan said: “We’re now looking at how our findings could be used to develop new ways to treat C.diff infections, such as using bacteriophages to attach to and kill C. diff cells - a promising potential alternative to traditional antibiotic drugs.”

Dr Paula Salgado, Senior Lecturer in Macromolecular Crystallography who led the research at Newcastle University said: “I started working on this structure more than 10 years ago, it’s been a long, hard journey but we got some really exciting results. Surprisingly, we found that the protein forming the outer layer, SlpA, packs very tightly, with very narrow openings that allow very few molecules to enter the cells. S-layers from other bacteria studied so far tend to have wider gaps, allowing bigger molecules to penetrate. This may explain the success of C.diff at defending itself against the antibiotics and immune system molecules sent to attack it.

“Excitingly, it also opens the possibility of developing drugs that target the interactions that make up the chain mail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell and kill it.”

One of the current challenges in our fight against infections is the growing ability bacteria have to resist the antibiotics that we use to try to kill them. Antibiotic, or more generally antimicrobial resistance (AMR), was declared by WHO as one of the top 10 global public health threats facing humanity.

Different bacteria have different mechanisms to resist antibiotics and some have multiple ways to avoid their action – the so-called superbugs. Included in these superbugs is C. difficile, a bacterium that infects the human gut and is resistant to all but three current drugs. Not only that, it actually becomes a problem when we take antibiotics, as the good bacteria in the gut are killed alongside those causing an infection and, as C. difficile is resistant, it can grow and cause diseases ranging from diarrhoea to death due to massive lesions in the gut. 

Another problem is the fact that the only way to treat C.difficile is to take antibiotics, so we restart the cycle and many people get recurrent infections.


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